EASTBIO CASE: Investigating the mechanisms underlying protective genetic associations with metabolic disease

This fully funded, 4-year PhD project is part of a competition funded by the BBSRC EASTBIO Doctoral Training Partnership.

This is a CASE studentship (Collaborative Awards in Science and Engineering). CASE studentships involve students enhancing their training by spending three to 18 months with a CASE partner in a workplace outside of the academic environment. The CASE partner for this project is Alnylam Pharmaceuticals Inc. Please note, your application may be shared with any external partners of this PhD Studentship.

Several studies including human SNP/GWAS, multi-omics data analysis and our own liver RNA-sequencing studies have identified a network of genes that are key drivers of liver lipid homeostasis and metabolic function (Morrice 2017, Krishnan 2018). Some of these genes have been characterised as encoding proteins involved in lipid metabolism pathways including regulation of lipid droplets e.g. the focus of this proposal HSD17B13 (our preprint in review); however most of these proteins have relatively unknown biological functions (Dong 2020). HSD17B13 is strongly linked to metabolic dysfunction-associated steatotic liver disease (MASLD), a common complication associated with obesity and thus requires further knowledge and drug discovery for targeting therapeutically.

Our data leading to a new hypothesis - we now have results that show specifically knocking down liver HSD17B13 leads to amelioration of the excess hepatic triglyceride storage thus providing definitive proof-of-concept evidence that this protein has an important biological function in lipid metabolism. The aim of this project will be to use state-of-the-art techniques to identify the unknown biological function/activity of this novel liver protein in hepatocytes, liver tissue from mice and 3D-organoids from adult human liver tissue. You will identify the protein components of the lipid droplet co-localised with HSD17B13 in cells. You will use confocal microscopy to determine the localisation of HSD17B13 and regulation of lipid droplet size in cells in response to lipogenic signalling networks. You will perform lipidomics using mass spectrometry with altered HSD17B13 protein levels to identify the role HSD17B13 in the liver. Overall, these studies will delineate a novel biological function of a liver protein involved in hepatic physiology and lipid metabolism and identify a novel physiological pathway to assist with drug discovery and clinical treatment of steatotic liver associated with obesity. In addition, the student will gain hands-on experience with the industrial collaborator in their pipeline of investigational RNAi therapeutics and use novel technology to silence potential therapeutic targets in vivo. The industrial collaborator's human genetics team has identified adipose-expressed genes where loss of function leads to reduced abdominal fat and the student will perform experiments to elucidate the molecular mechanisms driving this.

For further project information please contact the lead project supervisor by selecting the first listed name at the top of this advert and sending your enquiry.

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ELIGIBILITY:

Applicants should hold a minimum of a 2:1 UK Honours degree (or international equivalent) in a relevant subject. Those with a 2:2 UK Honours degree (or international equivalent) may be considered, provided they have (or are expected to achieve) a Distinction or Commendation at master’s level.

We encourage applications from all backgrounds and communities, and are committed to having a diverse, inclusive team.

All students must meet the eligibility criteria as outlined in the UKRI guidance on funding for postgraduate training and development. This guidance should be read in conjunction with the Terms and conditions for training funding – UKRI.

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APPLICATION PROCEDURE:

• Please visit this page for full application information: https://biology.ed.ac.uk/eastbio/how-to-apply
• Please send your completed EASTBIO application form, along with academic transcripts and certificates to [Email Address Removed]
• Please ensure that two references are submitted by the deadline using the EASTBIO reference form (available here). If the references are not included with your application, they must be sent directly to [Email Address Removed] with the subject line: "EASTBIO Reference – [Your Name]".
• It is the applicant’s responsibility to ensure that references are submitted by the deadline (17^th January). We will not request academic references on your behalf.
• Please ensure you submit all the required information and documentation. Due to workload constraints, we are unable to follow up on missing documents or process incomplete applications.
• If you require any additional assistance in submitting your application or have any queries about the application process, please don't hesitate to contact us at [Email Address Removed]